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1.
Exp Hematol Oncol ; 12(1): 94, 2023 Nov 09.
Article in English | MEDLINE | ID: mdl-37946295

ABSTRACT

Recurrence is one of the main causes of treatment failure in early-stage non-small cell lung cancer (NSCLC). However, there are no predictors of the recurrence of early-stage NSCLC, and the molecular mechanism of its recurrence is not clear. In this study, we used clinical sample analysis to demonstrate that low levels of expression of precursor surfactant protein B (pro-SFTPB) in primary NSCLC tissue compared to their adjacent tissues are closely correlated with recurrence and poor prognosis in early-stage NSCLC patients. In vitro and in vivo experiments showed that downregulation of pro-SFTPB expression activates the Akt pathway by upregulating PGK1, which promotes metastasis and tumorigenicity in NSCLC cells. We then demonstrated that pro-SFTPB suppresses the formation of the ADRM1/hRpn2/UCH37 complex by binding to ADRM1, which inhibits PGK1 deubiquitination, thus accelerating ubiquitin-mediated PGK1 degradation. In summary, our findings indicate that low expression of pro-SFTPB in primary NSCLC compared to their adjacent tissue has potential as a predictor of recurrence and poor prognosis in early-stage NSCLC. Mechanistically, downregulation of pro-SFTPB attenuates inhibition of ADRM1-deubiquitinated PGK1, resulting in elevated levels of PGK1 protein; this activates the Akt pathway, ultimately leading to the progression of early-stage NSCLC.

2.
Adv Sci (Weinh) ; 10(11): e2203573, 2023 04.
Article in English | MEDLINE | ID: mdl-36757050

ABSTRACT

Recurrence is a challenge to survival after the initial treatment of esophageal squamous cell carcinoma (ESCC). But, its mechanism remains elusive and there are currently no biomarkers to predict postoperative recurrence. Here, the possibility of sterile alpha motif domain-containing protein 9 (SAMD9) as a predictor of postoperative recurrence of ESCC is evaluated and the molecular mechanisms by which SAMD9 promotes ESCC recurrence are elucidated. The authors found that the high level of SAMD9 is correlated with postoperative recurrence and poor prognosis of ESCC. Overexpression of SAMD9 promotes tumor stemness, angiogenesis, and EMT, while downregulation of SAMD9 reduced these phenotypes. Mechanistically, it is found that SAMD9 stimulated ubiquitination-mediated glycogen synthase kinase-3 beta (GSK-3ß) degradation by interaction with myosin-9 (MYH9) and TNF receptor-associated factor 6 (TRAF6), which in turn activated Wnt/ß-catenin pathway. Further, the authors demonstrated that silencing SAMD9 inhibited lung metastasis and tumor formation in vivo. Finally, the authors found that silencing MYH9 or ß-catenin, or overexpressing GSK-3ß inhibited SAMD9-stimulated ESCC cell stemness, EMT, angiogenesis, metastasis, and tumorigenicity. Together, the findings indicate that the SAMD9/MYH9/GSK3ß/ß-catenin axis promotes ESCC postoperative recurrence and that SAMD9 is a crucial target for ESCC therapy. Additionally, SAMD9 has the potential as a predictor of postoperative recurrence in ESCC.


Subject(s)
Carcinoma, Squamous Cell , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Wnt Signaling Pathway , Humans , beta Catenin/metabolism , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/metabolism , Esophageal Neoplasms/genetics , Esophageal Neoplasms/metabolism , Esophageal Squamous Cell Carcinoma/genetics , Esophageal Squamous Cell Carcinoma/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Myosin Heavy Chains/genetics , Myosin Heavy Chains/metabolism , Wnt Signaling Pathway/genetics
3.
Pharmacol Res ; 187: 106636, 2023 01.
Article in English | MEDLINE | ID: mdl-36586643

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality and limited therapeutic options. The immune checkpoint PD1/PD-L1 axis is related to the pathogenesis of pulmonary fibrosis, and upregulated expression levels of PD-L1 have been demonstrated in IPF patients. However, the mechanism of PD-L1 in pulmonary fibrosis is not fully understood. Here, we demonstrated upregulated expression of PD-L1 in fibrotic lung tissues and sera of IPF patients. Bleomycin (BLM) treatment induced PD-L1 upregulation, EMT (Epithelial-Mesenchymal Transition) and fibrosis-like morphology changes in human pulmonary alveolar epithelial cells (HPAEpiCs). Silencing PD-L1 attenuated BLM-induced EMT and fibrosis-like morphology changes in HPAEpiCs. In addition, we identified that PD-L1 directly binds to vimentin and inhibits vimentin ubiquitination, thereby increasing vimentin levels in HPAEpiCs. Silencing of vimentin inhibited BLM- and PD-L1-induced fibrosis in HPAEpiCs. The correlation between PD-L1 and EMT or vimentin expression was further confirmed in clinical samples and animal models. Finally, we used BLM- and paraquat-induced pulmonary fibrosis animal models to confirm the anti-pulmonary fibrosis effects of PD-L1 silencing. Taken together, our findings suggest that upregulated PD-L1 stimulates EMT of alveolar epithelial cells by increasing vimentin levels by inhibiting vimentin ubiquitination, thereby contributing to pulmonary fibrosis.


Subject(s)
B7-H1 Antigen , Idiopathic Pulmonary Fibrosis , Animals , Humans , Up-Regulation , Vimentin/genetics , Vimentin/metabolism , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Lung , Idiopathic Pulmonary Fibrosis/chemically induced , Idiopathic Pulmonary Fibrosis/genetics , Idiopathic Pulmonary Fibrosis/metabolism , Epithelial-Mesenchymal Transition , Bleomycin
4.
J Phys Chem Lett ; 13(50): 11581-11594, 2022 Dec 22.
Article in English | MEDLINE | ID: mdl-36480578

ABSTRACT

Two-dimensional (2D) materials have attracted great attention mainly due to their unique physical properties and ability to fulfill the demands of future nanoscale devices. By performing high-throughput first-principles calculations combined with a semiempirical van der Waals dispersion correction, we have screened 73 direct- and 183 indirect-gap 2D nonmagnetic semiconductors from nearly 1000 monolayers according to the criteria for thermodynamic, mechanical, dynamic, and thermal stabilities and conductivity type. We present the calculated lattice constants, formation energy, Young's modulus, Poisson's ratio, shear modulus, anisotropic effective mass, band structure, band gap, ionization energy, electron affinity, and simulated scanning tunnel microscopy for each candidate meeting our criteria. The resulting 2D semiconductor database (2DSdb) can be accessed via the Web site https://materialsdb.cn/2dsdb/index.html. The 2DSdb provides an ideal platform for computational modeling and design of new 2D semiconductors and heterostructures in photocatalysis, nanoscale devices, and other applications. Further, a linear fitting model was proposed to evaluate band gap, ionization energy, and electron affinity of 2D semiconductors from the density functional theory (DFT) calculated data as initial input. This model can be as precise as hybrid DFT but with much lower computational cost.

5.
Thorac Cancer ; 12(10): 1558-1569, 2021 05.
Article in English | MEDLINE | ID: mdl-33755320

ABSTRACT

BACKGROUND: Recurrence is a major challenge in early-stage lung adenocarcinoma (LUAD) treatment. Here, we investigated the role and mechanism of high-mobility group AT-hook 1 (HMGA1) and glucose-regulated protein 75-kDa (GRP75) in stage I LUAD and evaluated their potential as biomarkers for predicting the recurrence and prognosis of stage I LUAD. METHODS: The TCGA dataset was used to investigate the clinical significance of HMGA1 and GRP75 in early-stage LUAD. The biological functions of HMGA1 and GRP75 in LUAD were investigated both in vitro and in vivo through overexpression and knockdown experiments. The interaction and regulation between HMGA1 and GRP75 were evaluated with coimmunoprecipitation and ubiquitination assays. The downstream signaling pathway of the GRP75/HMGA1 axis was investigated by mRNA-sequencing analysis. RESULTS: Both HMGA1 expression levels and GRP75 expression levels were associated with recurrence in stage I LUAD patients. In particular, HMGA1 had potential as an independent prognostic factor in stage I LUAD patients. Overexpression of GRP75 or HMGA1 significantly stimulated LUAD cell growth and metastasis, while silencing GRP75 or HMGA1 inhibited LUAD cell growth and metastasis in vitro and in vivo. Importantly, GRP75 inhibited ubiquitination-mediated HMGA1 degradation by directly binding to HMGA1, thereby causes HMGA1 upregulation in LUAD. In addition, the GRP75/HMGA1 axis played its role by activating JNK/c-JUN signaling in LUAD. CONCLUSIONS: The activation of GRP75/HMGA1/JNK/c-JUN signaling is an important mechanism that promotes the progression of stage I LUAD, and a high level of HMGA1 is a novel biomarker for predicting recurrence and a poor prognosis in stage I LUAD patients.


Subject(s)
Adenocarcinoma of Lung/metabolism , HMGA1a Protein/metabolism , HSP70 Heat-Shock Proteins/metabolism , Lung Neoplasms/metabolism , MAP Kinase Signaling System , Mitochondrial Proteins/metabolism , Mitogen-Activated Protein Kinase 8/metabolism , A549 Cells , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Animals , Disease Progression , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Neoplasm Staging , Prognosis , Transfection , Up-Regulation
6.
Mol Ther Nucleic Acids ; 16: 675-685, 2019 Jun 07.
Article in English | MEDLINE | ID: mdl-31121479

ABSTRACT

Dysregulated microRNAs (miRNAs) play crucial roles in the regulation of cancer stem cells (CSCs), and CSCs are closely associated with tumor initiation, metastasis, and recurrence. Here we found that miR-150-5p was significantly downregulated in CSCs of non-small-cell lung cancer (NSCLC) and its expression level was negatively correlated with disease progression and poor survival in patients with NSCLC. Inhibition of miR-150-5p increased the CSC population and sphere formation of NSCLC cells in vitro and stimulated NSCLC cell tumorigenicity and metastatic colonization in vivo. In contrast, miR-150-5p overexpression potently inhibited sphere-formed NSCLC cell tumor formation, metastatic colonization, and recurrence in xenograft models. Furthermore, we identified that miR-150-5p significantly inhibited wingless (Wnt)-ß-catenin signaling by simultaneously targeting glycogen synthase kinase 3 beta interacting protein (GSKIP) and ß-catenin in NSCLC cells. miR-150-5p also targeted high mobility group AT-hook 2 (HMGA2), another regulator of CSCs, and Wnt-ß-catenin signaling. The restoration of HMGA2 and ß-catenin blocked miR-150-5p overexpression-induced inhibition of CSC traits in NSCLC cells. These findings suggest that miR-150-5p functions as a CSC suppressor and that overexpression of miR-150-5p may be a novel strategy to inhibit CSC-induced metastasis and recurrence in NSCLC.

7.
J Thorac Dis ; 9(10): 3774-3781, 2017 Oct.
Article in English | MEDLINE | ID: mdl-29268385

ABSTRACT

BACKGROUND: Drug resistant Mycoplasma pneumoniae (MP) is a rising issue in the management of community-acquired pneumonia (CAP). Epidemiological monitoring is essential for identifying resistant patterns of MP isolates against various antibiotics in adult CAP patients. METHODS: This is a prospectively designed multicenter study conducted on adult patients with CAP visiting six teaching hospitals in the cities of Beijing, Shanghai and Guangzhou between September 2010 and June 2012. RESULTS: A total of 520 adult patients (mean age: 45.7±26.2 years) with CAP visiting teaching hospitals in the cities of Beijing, Shanghai and Guangzhou were included. Of the 520 patients, only 75 (14.42%) were confirmed MP positive by means of culture and real-time PCR methods. Quinolones were the most common initially prescribed antimicrobial, followed by ß-lactams and ß-lactams plus quinolones. Macrolide resistance was as high as 80% and 72% against erythromycin (ERY) and azithromycin (AZM) respectively, which were associated with the A2063G transition mutation in domain V of the 23S ribosomal RNA (rRNA) gene. Six strains with mild to moderate ERY-resistant level were still susceptible to AZM. Tetracycline (TET), minocycline (MIN) and quinolones [moxifloxacin (MOX) and fluoroquinolones] had no signs of resistance. CONCLUSIONS: High resistance was observed with macrolides, whereas, none of the MP strains were resistant to fluoroquinolones and TET. Hence, macrolide resistant MP (MRMP)_infections could be well treated with fluoroquinolones. However, few isolated strains had minimal inhibitory concentration (MIC) values on the edge of resistance to quinolones, alarming a quinolone-resistant MP in the near future.

8.
Mol Ther Nucleic Acids ; 9: 145-154, 2017 Dec 15.
Article in English | MEDLINE | ID: mdl-29246293

ABSTRACT

Dysregulated miRNAs play important role in K-ras mutation or smoking caused lung tumorigenesis. Here, we investigate the role and mechanism of miR-124 in K-ras mutation or smoking-caused lung tumorigenesis and evaluate the therapeutic potential of miR-124 agomiR in K-ras mutation or smoking-caused lung cancer treatment. Our data show that smoking suppresses miR-124 expression, and decreased miR-124 expression is inversely correlated with the p-Akt level and predicts poor overall survival in non-small-cell lung cancer (NSCLC) patients. The overexpression of miR-124 suppressed NSCLC growth by inhibiting the Akt pathway by targeting Akt1 and Akt2. In addition, the systemic delivery of miR-124 agomiR dramatically suppressed tumorigenesis in both NNK-induced lung cancer model and K-rasLA1 transgenic mice by increasing apoptosis and inhibiting cell proliferation. Our findings suggest that smoking inhibits the expression of miR-124, and decreased miR-124 contributes to Akt activation, thereby promoting NSCLC progression. Our findings also represent a novel potential therapeutic strategy for lung cancer.

9.
Chin Med J (Engl) ; 128(20): 2707-13, 2015 Oct 20.
Article in English | MEDLINE | ID: mdl-26481734

ABSTRACT

BACKGROUND: Healthcare-associated pneumonia (HCAP) is associated with drug-resistant pathogens and high mortality, and there is no clear evidence that this is due to inappropriate antibiotic therapy. This study was to elucidate the clinical features, pathogens, therapy, and outcomes of HCAP, and to clarify the risk factors for drug-resistant pathogens and prognosis. METHODS: Retrospective observational study among hospitalized patients with HCAP over 10 years. The primary outcome was 30-day all-cause hospital mortality after admission. Demographics (age, gender, clinical features, and comorbidities), dates of admission, discharge and/or death, hospitalization costs, microbiological results, chest imaging studies, and CURB-65 were analyzed. Antibiotics, admission to Intensive Care Unit (ICU), mechanical ventilation, and pneumonia prognosis were recorded. Patients were dichotomized based on CURB-65 (low- vs. high-risk). RESULTS: Among 612 patients (mean age of 70.7 years), 88.4% had at least one comorbidity. Commonly detected pathogens were Acinetobacter baumannii, Pseudomonas aeruginosa, and coagulase-negative staphylococci. Initial monotherapy with ß-lactam antibiotics was the most common initial therapy (50%). Mean age, length of stay, hospitalization expenses, ICU admission, mechanical ventilation use, malignancies, and detection rate for P. aeruginosa, and Staphylococcus aureus were higher in the high-risk group compared with the low-risk group. CURB-65 ≥3, malignancies, and mechanical ventilation were associated with an increased mortality. Logistic regression analysis showed that cerebrovascular diseases and being bedridden were independent risk factors for HCAP. CONCLUSION: Initial treatment of HCAP with broad-spectrum antibiotics could be an appropriate approach. CURB-65 ≥3, malignancies, and mechanical ventilation may result in an increased mortality.


Subject(s)
Community-Acquired Infections/pathology , Pneumonia/pathology , Acinetobacter baumannii/pathogenicity , Aged , Anti-Bacterial Agents/therapeutic use , Community-Acquired Infections/drug therapy , Community-Acquired Infections/microbiology , Female , Hospital Mortality , Hospitalization , Humans , Male , Middle Aged , Pneumonia/drug therapy , Pneumonia/microbiology , Pseudomonas aeruginosa/pathogenicity , Retrospective Studies , Staphylococcus aureus/pathogenicity
10.
Clin Cancer Res ; 20(17): 4705-16, 2014 Sep 01.
Article in English | MEDLINE | ID: mdl-24958806

ABSTRACT

PURPOSE: The aim of the present study is to investigate the role and mechanism of miR216a in non-small-cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: The expression of miR216a in NSCLC cell lines and from NSCLC patient specimens was measured by real-time qRT-PCR. The correlation between gene expression and patient survival was analyzed using Kaplan-Meier methods. The effects of miR216a on NSCLC cell growth and metastasis were examined both in vitro and in vivo by overexpressing or inhibiting miR216a. Finally, the effect of miR216a on chemoresistance was investigated by MTT assay and flow cytometry. RESULTS: miR216a expression was downregulated in specimens from patients with NSCLC compared with corresponding nontumor lung tissues. Clinical data indicate that decreased miR216a expression is inversely correlated with cancer stage, metastasis, and poor survival in patients with NSCLC. Our data also show that overexpression of miR216a suppresses NSCLC cell growth and metastasis, and enhances cisplatin-induced cell growth inhibition and apoptosis. In contrast, inhibition of miR216a stimulates NSCLC cell growth and metastasis, and suppresses cisplatin-induced cell growth inhibition and apoptosis. Furthermore, we demonstrate that miR216a exerts its role by directly targeting eIF4B and ZEB1. CONCLUSION: Our findings suggest that miR216a is a cancer suppressor miRNA and that overexpression of miR216a is a novel NSCLC treatment strategy. In addition, our clinical data indicate that miR216a may be a useful biomarker for predicting NSCLC progression.


Subject(s)
Apoptosis/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Cell Proliferation/genetics , MicroRNAs/biosynthesis , Aged , Carcinoma, Non-Small-Cell Lung/pathology , Female , Gene Expression Regulation, Neoplastic , Humans , Kaplan-Meier Estimate , Lymphatic Metastasis/genetics , Lymphatic Metastasis/pathology , Male , MicroRNAs/antagonists & inhibitors , MicroRNAs/genetics , Middle Aged , Prognosis
11.
Thorac Cancer ; 4(2): 186-190, 2013 May.
Article in English | MEDLINE | ID: mdl-28920208

ABSTRACT

Although the sensitivity can reach 99%, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a significantly high false negative rate for diagnosis and staging of thoracic malignancy. We performed this retrospective study to investigate the causes of false negative results and to improve the efficacy and accuracy of EBUS-TBNA. We reviewed all patients suspected of intrapulmonary or mediastinal malignancy who undertook EBUS-TBNA between July 2009 and August 2012 in Chinese PLA general hospital. We retrieved the pathological results of EBUS-TBNA and video-assisted thoracic surgery (VATS) and follow-up data. The sensitivity, specificity, positive predictive value and negative predictive value were calculated. 185 patients were included in this study. Diagnosis of malignancy was established on 172 patients by EBUS-TBNA, and 8 patients with negative EBUS-TBNA result gained their final diagnosis of malignancy via VATS. The sensitivity, specificity, negative predictive value and accuracy for diagnosis of malignancy for EBUS-TBNA were 96%, 100%, 33% and 96% respectively. Inadequacy of the EBUS-TBNA specimens, internal necrosis in the lymph nodes and rare cancer types contributed to the false negative EBUS-TBNA results. VATS is obligatory to explain the negative results of EBUS-TBNA in patients suspected of malignancy.

12.
Zhonghua Jie He He Hu Xi Za Zhi ; 36(12): 954-8, 2013 Dec.
Article in Chinese | MEDLINE | ID: mdl-24503430

ABSTRACT

OBJECTIVE: To explore the tendency of macrolide resistance in Mycoplasma pneumoniae infection in community-acquired pneumonia (CAP) patients in Beijing. METHODS: Adult CAP patients of ≥ 18 yrs were enrolled in 3 medical centers in Beijing , China. Throat swab samples were taken from all the patients to perform the culture of M. pneumoniae . All the isolated M. pneumoniae strains were subjected to susceptibility evaluation for 6 agents, including macrolides such as erythromycin and azithromycin. In strains showing macrolide resistance, the 23S rRNA gene was analyzed. RESULTS: A total 53 strains of M. pneumoniae were isolated from 321 enrolled patients. Thirty-eight of the isolated strains (71.7%) were resistant to erythromycin and 32 of them (60.4%) were resistant to azithromycin. Six strains with moderate or low level of erythromycin-resistance were still susceptible to azithromycin. No fluoroquinolone-resistant or tetracycline-resistant strains were observed in our study. Point transition of A2063G in the 23S ribosomal RNA gene was the main reason for the high prevalence of macrolide resistance. CONCLUSIONS: The prevalence of macrolide resistance in M. pneumoniae is very high in adult CAP patients in Beijing. Studies are needed to clarify the clinical meaning of prevalence of macrolide-resistant M. pneumoniae in adults CAP patients.


Subject(s)
Anti-Bacterial Agents/pharmacology , Community-Acquired Infections/microbiology , Drug Resistance, Bacterial , Macrolides/pharmacology , Mycoplasma pneumoniae/drug effects , Pneumonia, Mycoplasma/microbiology , Adult , Aged , China/epidemiology , Community-Acquired Infections/drug therapy , Community-Acquired Infections/epidemiology , DNA, Bacterial/genetics , Drug Resistance, Bacterial/genetics , Erythromycin/pharmacology , Female , Humans , Male , Microbial Sensitivity Tests , Middle Aged , Mutation , Mycoplasma pneumoniae/genetics , Mycoplasma pneumoniae/isolation & purification , Pneumonia, Mycoplasma/drug therapy , Pneumonia, Mycoplasma/epidemiology , Polymerase Chain Reaction , RNA, Ribosomal, 23S/genetics , Sequence Analysis, DNA
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